There is a highly significant increase in mortality from cardiovascular disease due to accelerated development of atherosclerosis and vascular calcification in people with chronic kidney disease. Traditional risk factors for cardiovascular disease don't entirely explain these accelerated vascular pathologies. We have shown that there is accelerated development of atherosclerosis and vascular calcification in mice that are deficient in osteoprotegerin, a decoy receptor for the receptor activator of NFkB ligand (RANKL). RANK-RANKL plays an essential role in bone homeostasis by stimulating the differentiation of osteoclasts. We have also shown that uremic LDLR-/- mice fed a high fat diet have accelerated atherosclerotic lesion development and increased expression of RANK in the aorta. Furthermore, treatment of macrophages and dendritic cells with RANKL stimulates the secretion of pro-inflammatory cytokines. We now hypothesize that the accelerated development of atherosclerosis and vascular calcification in chronic kidney disease may be due to increased RANKL and the stimulation of RANK signaling in macrophages and dendritic cells. We will test this hypothesis with 2 specific aims. In aim 1, we will determine the signature of secreted proteins using shot-gun proteomics and the profile of expressed genes using microarrays in macrophages and dendritic cells from uremic mice and monocytes from people with chronic kidney disease as well as in macrophages and dendritic cells treated with RANKL in order to determine which pro-atherosclerotic and pro-calcification pathways are activated and may account for the accelerated vascular disease. In the second aim, we will transplant bone marrow from mice that are deficient in RANK into uremic mice and treat uremic mice with an anti-RANKL therapeutic (OPG-Fc) to determine whether blocking RANKL can protect against the accelerated atherosclerosis and vascular calcification that occurs with chronic kidney disease. PUBLIC HEALTH RELEVANCE: Public Health Relevance Statement It is now estimated that over 15% of the population of the United States have chronic kidney disease (CKD). There is a highly significant increase in mortality from cardiovascular disease due to accelerated development of atherosclerosis and vascular calcification in people with CKD and traditional risk factors for cardiovascular disease do not entirely explain this increase in cardiovascular mortality. Thus, there is a continuing need to define and explore new pathways associated with CKD that will help explain the increased cardiovascular risk and lead to new and unique therapeutic approaches.